1. Field of the Invention
This invention is directed to the inhibition of cell proliferation and/or cell matrix production and/or cell movement (chemotaxis) and/or T cell activation and proliferation using of quinoline/quinoxaline compounds which are useful protein tvrosine kinase inhibitors (TKIs).
Cellular signaling is mediated through a system of interactions which include cell-cell contact or cell-matrix contact or extracellular receptor-substrate contact. The extracellular signal is often communicated to other parts of the cell via a tyrosine kinase mediated phosphorylation event which affects substrate proteins downstream of the cell membrane bound signaling complex. A specific set of receptor-enzymes such as the insulin receptor, epidermal growth factor receptor (EGF-R) or platelet-derived growth factor receptor (PDGF-R) are examples of tyrosine kinase enzymes which are involved in cellular signaling. Autophosphorylation of the enzyme is required for efficient enzyme-mediated phosphorylation of substrate proteins containing tyrosine residues. These substrates are known to be responsible for a variety of cellular events including cellular proliferation, cellular matrix production, cellular migration and apoptosis to name a few.
It is understood that a large number of disease states are caused by either uncontrolled reproduction of cells or overproduction of matrix or poorly regulated programmed cell death (apoptosis). These disease states involve a variety of cell types and include disorders such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and restenosis occurring subsequent to angioplasty of the coronary, femoral or kidney arteries or, fibroproliferative disease such as in arthritis, fibrosis of the lung, kidney and liver. In addition, deregulated cellular proliferative conditions follow from coronary bypass surgery. The inhibition of tyrosine kinase activity is believed to have utility in the control of uncontrolled reproduction of cells or overproduction of matrix or poorly regulated programmed cell death (apoptosis).
It is also known that certain tyrosine kinase inhibitors can interact with more than one type of tyrosine kinase enzyme. Several tyrosine kinase enzymes are critical for the normal function of the body. For instance, it would be undesirable to inhibit insulin action in most normal circumstances. Therefore, compounds which inhibit PDGF-R tyrosine kinase activity at concentrations less than the concentrations effective in inhibiting the insulin receptor kinase could provide valuable agents for the selective treatment of diseases characterized by cell proliferation and/or cell matrix production and/or cell movement (chemotaxis) such as restenosis.
This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation, extracellular matrix production, chemotaxis, the control of abnormal cell growth and cell inflammatory response. More specifically, this invention relates to the use of substituted quinoxaline compounds which exhibit selective inhibition of differentiation, proliferation or mediator release by effectively inhibiting platelet-derived growth factor-receptor (PDGF-R) tyrosine kinase activity and/or Lck tyrosinie kinase activity.
2. Reported Developments
A number of literature reports describe tyrosine kinase inhibitors which are selective for tyrosine kinase receptor enzymes such as EGF-R or PDGF-R or non-receptor cytosolic tyrosine kinase enzymes such as v-abl p56lck or c-src. Recent reviews by Spada and Myers (Exp. Opin. Ther. Patents 1995, 5(8), 805) and Bridges (Exp. Opin. Ther. Patents 1995, 5(12), 1245) summarize the literature for tyrosine kinase inhibitors and EGF-R selective inhibitors respectively. Additionally Law and Lydon have summarized the anticancer potential of tyrosine kinase inhibitors (Emerging Drugs: The Prospect For Improved Medicines 1996, 241-260).
Known inhibitors of PDGF-R tyrosine kinase activity includes quinoline-based inhibitors reported by Maguire et al. (J. Med. Chem. 1994, 37, 2129), and by Dolle et al. (J. Med. Clem. 1994, 37, 2627). A class of phenylamino-pyrimidine-based inhibitors was recently reported by Traxler et al. in EP 564409 and by Zimmerman, J.; and Traxler. P. et al. (Biorg. and Med. Chem. Lett. 1996, 6(11), 1221-1226) and by Buchdunger, E. et al. (Proc. Nat. Acad. Sci. 1995, 92, 2558). Despite the progress in the field there are no agents from these classes of compounds that have been approved for use in humans for treating proliferative disease.
The correlation between the multifactorial disease of restenosis with PDGF and PDGF-R is well-documented throughout the scientific literature. However, recent developments into the understanding of fibrotic diseases of the lung (Antoniades, H. N.; et al. J. Clin. Invest. 1990, 86, 1055), kidney and liver (Peterson, T. C. Hepatology, 1993, 17, 486) have also implicated PDGF and PDGF-R as playing a role. For instance glomerulonephritis is a major cause of renal failure and PDGF has been identified to be a potent mitogen for mesangial cells in vitro as demonstrated by Shultz et al. (Am. J. Physiol. 1988, 255, F674) and by Floege, et al. (Clin. Exp. Immun. 1991, 86, 334). It has been reported by Thornton, S. C.; et al. (Clin. Exp. Immun. 1991, 86, 79) that TNF-alpha and PDGF (obtained from human rheumatoid arthritis patients) are the major cytokines involved in proliferation of synovial cells. Furthermore, specific tumor cell types have been identified (see Silver, B. J., BioFactors, 1992, 3, 217) such as glioblastoma and Kaposi""s sarcoma which overexpress either the PDGF protein or receptor thus leading to the uncontrolled growth of cancer cells via an autocrine or paracrine mechanism. Therefore, it is anticipated that a PDGF tyrosine kinase inhibitor would be useful in treating a variety of seemingly unrelated human disease conditions that can be characterized by the involvement of PDGF and or PDGF-R in their etiology.
The role of various non-receptor tyrosine kinases such as p56lck (hereinafter xe2x80x9cLckxe2x80x9d) in inflammation-related conditions involving T cell activation and proliferation has been reviewed by Hanke, et al (Inflamm. Res. 1995, 44, 357) and by Bolen and Brugge (Ann. Rev. Immunol., 1997, 15, 371). These inflammatory conditions include allergy, autoimmune disease, rheumatoid arthritis and transplant rejection. Another recent review summarizes various classes of tyrosine kinase inhibitors including compounds having Lek inhibitory activity (Groundwater, et. al Progress in Medicinal Chemistry, 1996, 33, 233). Inhibitors of Lck tyrosine kinase activity include several natural products which are generally non-selective tyrosine kinase inhibitors such as staurosporine, genistein, certain flavones and erbstatin. Damnacanthol was recently reported to be a low nM inhibitor of Lck (Faltynek, et. al, Biochemistry, 1995, 34, 12404). Examples of synthetic Lck inhibitors include: a series of dihydroxy-isoquinoline inhibitors reported as having low micromolai to submicromolar activity (Burke, et. al J. Med. Chem. 1993, 36, 425); and a quinoline derivative found to be much less active having an Lck IC50 of 610 micromolar. Researchers have also disclosed a series of 4-substituted quinazolines that inhibit Lck in the low micromolar to submicromolar range (Myers et al. WO95/15758 and Myers, et. al Bioorg. Med. Chem. Lett. 1997, 7.417). Researchers at Pfizer (Hanke, et. al J. Biol. Chem. 1996, 271, 695) have disclosed twvo specific pyrazolopyrimidine inhibitors known as PP1 and PP2 which have low nanomolar potency against Lck and Fyn. (another Src-family kinase). No Lck inhibitory has been reported regarding quinoline or quinoxaline based compounds. Therefore, it is anticipated that a quinoline or quinoxaline based inhibitor of Lck tyrosine kinase activity could be useful in treating a variety of seemingly unrelated human disease conditions that can be characterized by the involvement of Lek tyrosine kinase signaling in their etiology.
This invention is directed to a compound of formula I: 
wherein
X is L1OH or L2Z2;
L1 is (CR3aR3b)1 or (CR3aR3b)mxe2x80x94Z3xe2x80x94(CR3xe2x80x2aR3xe2x80x2b)n;
L2 is (CR3aR3b)pxe2x80x94Z4xe2x80x94(CR3xe2x80x2aR3xe2x80x2b)q or ethenyl;
Z1 is CH or N;
Z2 is optionally substituted hydroxycycloalkyl, optionally substituted hydroxycycloalkenyl, optionally substituted hydroxyheterocyclyl or optionally substituted hydroxyheterocyclenyl;
Z3 is O, NR4, S, SO or SO2;
Z4 is O, NR4, S, SO, SO2 or a bond;
m is 0 or 1;
n is 2 or 3, and n+m=2 or 3;
p and q are independently 0, 1, 2, 3 or 4, and p+q=0, 1, 2, 3 or 4 when Z4 is a bond, and p+q=0, 1, 2 or 3 when Z4 is other than a bond:
r is 2, 3 or 4;
R1a and R1b are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted atyloxy, optionally substituted heteroaryloxy, cyano, R5R6Nxe2x80x94 or acyl R5Nxe2x80x94, or one of R1a and R1b is hydrogen or halo and the other is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted arvloxy, optionally substituted heteroaryloxy, cyano, R5R6Nxe2x80x94 or acyl R5Nxe2x80x94.
R1c is hydrogen, optionally substituted alkyl optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, halo, cyano, R5R6Nxe2x80x94 or acyl R5Nxe2x80x94;
R3a, R3b, R3xe2x80x2a and R3xe2x80x2b are independently hydrogen or alkyl:
R4 is hydrogen, alkyl or acyl; and
R5 and R6 are independently hydrogen or alkyl, or R5 and R6 taken together with the nitrogen atom to which R5 and R6 are attached form azaheterocyclyl, or
an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.
Another aspect of the invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. The invention is also directed to intermediates usefuil in preparing compounds of formula I, methods for the preparation of the intermediates and compounds of formula I, and the use of a compound of formula I for treating a patient suffering from or subject to disorders/conditions involving cellular differentiation, proliferation, extracellular matrix production or mediator release.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
Definitions
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cEffective amountxe2x80x9d means an amount of compound of the present invention effective in inhibiting PDGF-R tyrosine kinase activity and/or Lck tyrosine kinase activity, and thus producing the desired therapeutic effect.
xe2x80x9cAlkylxe2x80x9d means aliphatic hydrocarbon group which may be branched-or straight-chained having about 1 to about 10 carbon atoms. Preferred alkyl is xe2x80x9clower-alkylxe2x80x9d having about 1 to about 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxyv halo, carboxy, hydroxy or R5R6Nxe2x80x94. Examples of alkyl include methyl, fluoromethyl, difluorom ethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 10 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 6 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group may be substituted by carbalkoxy. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cEthylenylxe2x80x9d means a xe2x80x94CHxe2x95x90CHxe2x80x94 group.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. The cycloalkyl group may be substituted by one or more, preferably one to three, more preferably one to two, of the following xe2x80x9ccycloalkyl substitlientsxe2x80x9d, alkyl, hydroxy, acyloxy, alkoxy, halo, R5R6Nxe2x80x94, acyl R5Nxe2x80x94, carboxy or R5R6NCOxe2x80x94, substituents, more preferred substituents are alkyl, hydroxy, acyloxy, alkoxy, and R5R6NCOxe2x80x94. Furthermore, when the cycloalkyl group is substituted with at least two hydroxy substituents, then at least two of the liydroxy substituents may be ketalated or acetalated with an aldehyde or ketone of one to six carbon atoms to form the corresponding ketal or acetal. xe2x80x9cHydroxycycloalkylxe2x80x9d means HO-cycloalkyl wherein the cycloalkyl may be substituted as noted. When the hydroxycycloalkyl group is derived from a cycloalkyl group which is also substituted with hydroxy, two of the hydroxy substituents may be ketalated or acetalated with an aldehyde or ketone of one to six carbon atoms to form the corresponding ketal or acetal. Ketalization of a gem-diol results in formation of a spiro fused ring system. A preferred spiro cycloalkyl ring is 1, 4-dioxaspiro[4, 5]dec-8-yl. Preferred unsubstituted or substituted monocyclic cycloalkyl rings include cyclopentyl, hydroxycyclopentyl, fluorocyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxymethylcyclohexyl and cycloheptyl; more preferred are hydroxycyclohexyl and hydroxycyclopentyl. Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl, [2.2.1]bicycloheptanyl (norbornyl), hydroxy[2.2.1]bicyclolieptanyl (hydroxynorbornyl), [2.2.2]bicyclooctanyl and hydroxy[2.2.2]bicyclooctanyl: more preferred are hydroxy[2.2.1]bicycloheptanyl (hydroxynorbornyl), and hydroxy[2.2.2]bicyclooctanyl.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. The cycloalkenyl group may be substituted by one or more, preferably one to three, more preferably one to two cycloalkyl substituents as described above. xe2x80x9cHydroxycycloalkenylxe2x80x9d means HO-cycloalkenyl wherein the cycloalkyl may be substituted as noted. Preferred unsubstituted or substituted monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, hydroxycyclopentenyl, hydroxycyclohexenyl and cycloheptenyl; more preferred is hydroxycyclopenitenyl and hydroxycyclohexenyl. Preferred multicyclic cycloalkenyl rings include [2.2.1]bicycloheptenyl (norbornenyl) and [2.2.2]bicyclooctenyl.
xe2x80x9cArylxe2x80x9d means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl croup substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes hydrogen hydroxy, halo, alkyl, alkoxy, carboxy, alkoxycarbonyl or Y1Y2NCO-, wherein Y1 and Y2 are independently hydrogen or alkyl. Preferred aryl group substituenits include hydrogen, halo and alkoxy.
xe2x80x9cHeteroarylxe2x80x9d means about a 5- to about a 10- membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. The xe2x80x9cheteroarylxe2x80x9d may also be substituted by one or more of the above-mentioned xe2x80x9caryl group substituentsxe2x80x9d. Exemplary heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo[2, 1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl and isoquinolinyl. xe2x80x9cHeterocyclylxe2x80x9d means an about 4 to about 10 member monocyclic or multicyclic ring system wherein one or more of the atoms in the ring system is an element other than carbon chosen amongst nitrogen, oxygen or sulfur. The heterocyclyl group may be substituted by one or more, preferably one to three, more preferably one to two cycloalkyl substituents as described above. xe2x80x9cHydroxyheterocyclylxe2x80x9d means HO-heterocyclyl wherein the heterocyclyl may be substituted as noted. xe2x80x9cAzaheterocyclylxe2x80x9d means a heterocyclyl as noted herein wherein at least one of the ring atoms is nitrogen. Exemplary heterocyclyl moieties include quinuclidyl, pentamethylenesulfide, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl or 7-oxabicyclo[2.2.1]heptanyl.
xe2x80x9cHeterocyclylcarbonyloxyxe2x80x9d means a heterocyclyl group as hefined herein which is attached to the parent molecular moiety through a carbonyloxy (xe2x80x94C(O)Oxe2x80x94) group. The heterocyclyly moiety is optionally substituted by one or more, preferably one to three, more preferably one cycloalkyl substituents as defined above. A representative heterocyclylcarbonyloxy is [1,4xe2x80x2]-bipiperidin-1xe2x80x2-ylcarbonyloxy.
xe2x80x9cHeterocyclenylxe2x80x9d means a heterocyclyl ring system as defined herein which contains at least one carbon-carbon or carbon-nitrogen double bond. The heterocyclenyl group may be substituted by one or more, preferably one to three, more preferably one to two cycloalkyl substituents as described above. xe2x80x9cHydroxyheterocyclenylxe2x80x9d means HO-heterocyclenyl wherein the heterocyclenyl may be substituted as noted. xe2x80x9cAzaheterocyclenylxe2x80x9d means a heterocyclenyl as noted herein wherein at least one of the ring atoms is nitrogen. Representative monocyclic heterocyclenyl groups include 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1, 2, 3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 3,4-dihydro-2H-pyran, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-metbylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the alkyl group is as previously described. Exemplary groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkylxe2x80x94Oxe2x80x94 group in which the alkyl group is as previously described. Preferred alkoxy is xe2x80x9clower alkoxyxe2x80x9d having about 1 to about 6 carbon atoms. The alkoxy may be optionally substituted by one or more amino, alkoxy, carboxy, alkoxycarbonyl, carboxyaryl, carbamoyl or heterocyclyl groups. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy. i-propoxy, n-butoxy, heptoxy, 2-(morpholin-4-yl)ethoxy, 2-(ethoxy)etlhoxy, 2-(4-methylpiperazin-1-yl)ethoxy, carbamoyl, N-methylcarbamoyl. N,N-dimethylcarbamoyl, carboxymethoxy and methoxycarbonylmethoxy.
xe2x80x9cCycloalkyloxyxe2x80x9d means a cycloalkyl-Oxe2x80x94 group in which the cycloalkyl group is as previously described. Exemplary cycloalkyloxy groups include cyclopentyloxy, cyclolhexyloxy, hydrocyclopentyloxy and hydroxycyclohexyloxy.
xe2x80x9cHeterocyclyloxyxe2x80x9d means a heterocyclyl-Oxe2x80x94 group in which the heterocyclyl group is as previously described. Exemplary heterocyclyloxy groups include quinuclidyloxy, pentamethylenesultideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy or 7-oxabicyclo[2.2.1 ]heptanyloxy, hydroxytetrahydropyranyloxy and hydroxy-7-oxabicyclo[2.2.1]heptanyloxy.
xe2x80x9cAryloxyxe2x80x9d means aryl-Oxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cHeteroaryloxyxe2x80x9d means heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cAcyloxyxe2x80x9d means an acyl-Oxe2x80x94 group in which the acyl group is as previously described.
xe2x80x9cCarboxyxe2x80x9d means a HO(O)Cxe2x80x94 (carboxylic acid) group.
xe2x80x9cR5R6Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein R5 and R6 are as previously described. Exemplary groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino and diethylamino.
xe2x80x9cR5R6NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein R5 and R6 are as previously described. Exemplary groups are carbamoyl (H2NCOxe2x80x94), N-methylcarbamoyl (MeNHCOxe2x80x94) and N,N-dimethylaminocarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cAcylR5Nxe2x80x94xe2x80x9d means an acylamino group wherein R5 and acyl are as defined herein.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
xe2x80x9cProdrugxe2x80x9d means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use, including ketal, ester and zwitterionic forms. A prodrug is transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
xe2x80x9cSolvatexe2x80x9d means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. xe2x80x9cSolvatexe2x80x9d encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like. xe2x80x9cHydratexe2x80x9d is a solvate wherein tle solvent molecule(s) islare H2O.
Preferred Embodiments
A preferred compound aspect of the invention is a compound of formula I wherein
L1 is (CR3aR3b)mxe2x80x94Z3xe2x80x94(CRxe2x80x2aR3xe2x80x2b)n;
L2 is (CR3aR3b)pxe2x80x94Z4xe2x80x94(CR3xe2x80x2aR3xe2x80x2b)q;
Z2 is optionally substituted hydroxycycloalkyl or optionally substituted hydroxyheterocyclyl;
Z4 is O and NR4;
m is 0;
n is 2 or 3;
p+q=0 or 1;
R1a and R1b are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy or R5R6N, or one of R1a and R1b is hydrogen or halo;
R1c is hydrogen, optionally substituted alkyl or optionally substituted alkoxy;
R3a, R3b, R3xe2x80x2a and R3xe2x80x2b are independently hydrogen or lower alkyl:
R4 is hydrogen; and
R5 R6 taken together with the nitrogen atom to which R5 and R6 are attached form azaheterocyclyl, or
an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.
Another preferred compound aspect of the invention is a compound of formula I wherein
X is L2Z2;
L2 is (CR3aR3b)pxe2x80x94Z4xe2x80x94(CR3xe2x80x2aR3xe2x80x2b)q;
Z2 is optionally substituted hydroxycycloalkyl;
Z4 is O and NR4;
p is 0;
q is 0 or 1;
R1a and R1b are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy or optionally substituted heterocyclyloxy, or one of R1a and R1b is hydrogen or halo and the other of R1a and R1b is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy or optionally substituted heterocyclyloxy;
R1c is hydrogen;
R3xe2x80x2a and R3xe2x80x2b are independently hydrogen; and
R4 is hydrogen, or
an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.
Another preferred compound aspect of the invention is a compound of formula I wherein R1a and R1b are independently optionally hydroxy substituted lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy heterocyclyloxy, or one of R1a and R1b is hydrogen or halo and the other of R1a and R1b is optionally hydroxy substituted lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy.
Another preferred compound aspect of the invention is a compound of formula I wherein R1a and R1b are independently heterocyclylcarbonyloxy or optionally substituted lower alkoxy; more preferably, the lower alkoxy is methoxy or ethoxy.
Another preferred compound aspect of the invention is a compound of formula I wherein R1a and R1b are lower alkyl; more preferably the lower alkyl is methyl or ethyl.
Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is lower alkoxy, and the other of R1a and R1b is halo; more preferably the lower alkoxy is methoxy or ethoxy, and the halo is chloro or bromo.
Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is lower alkyl, and the other of R1a and R1b is lower alkoxy; more preferably the lower alkoxy is methoxy or ethoxy, and the lower alkyl is methyl or ethyl.
Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is lower alkoxy, and the other of R1a and R1b is cycloalkyloxy; more preferably the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy.
Another preferred compound aspect of the invention is a compound of formula I whereein one of R1a and R1b is hydrogen, and the other of R1a and R1b is lower alkoxy, cycloalkyloxy or heterocyclyloxy; more preferably the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy, and the heterocyclyloxy is furanyloxy.
Another preferred compound aspect of the invention is a compound of formula I wherein R1a and R1b are lower alkoxy wherein the lower alkoxy is optionally substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl.
Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is unsubstituted lower alkoxy and the other of R1a and R1b optionally substituted heterocyclylcarbonyloxy or is lower alkoxy substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl.
Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is methoxy and the other of R1a and R1b is [1, 4xe2x80x2]-bipiperadin-1xe2x80x2-ylcarbonyloxy, 2-(ethoxy)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, carboxymethoxy, methoxycarbonylmetlhoxy, aminocarbonylmethoxy, N-methylaminocarbonylmethoxy or N,N-dimethylaminocarbonylmethoxy.
Another preferred compound aspect of the invention is a compound of formula I wherein R1c is hydrogen, lower alkyl or lower alkoxy; more preferably the lower alkoxy is methoxy or ethoxy.
Another preferred compound aspect of the invention is a compound of formula I wherein Z1 is CH.
Another preferred compound aspect of the invention is a compound of formula I wherein Z1 is N.
Another preferred compound aspect of the invention is a compound of formula I wherein Z2 is optionally substituted hydroxycycloalkyl.
Another preferred compound aspect of the invention is a compound of formula I wherein p and q are 0.
Another preferred compound aspect of the invention is a compound of formula I wherein p+q=1.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is O.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is O, and p and q are 0.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is O, and p+q=1.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is NR4.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is NR4, and p and q are 0.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is NR4. and m+n=1.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is S.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is S, and p and q are 0.
Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is S, and
Another preferred compound aspect of the invention is a compound of formula I wherein Z2 is (hydroxy or alkyl) substituted hydroxycycloalkyl, more preferred is (lower alkyl)hydroxycycloalkyl.
Preferred compounds according to the invention are selected from the following species:
trans-4-(7-Chloro-6-methoxyquinoxalin-2-ylamino)-cyclohexanol;
trans-4-(6-Chloro-7-methoxyquinoxalin-2-ylamino)-cyclohexanol;
trans-4-(6, 7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;
cis-4-(6, 7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;
(2endo,5exo)-5-(6, 7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;
(2exo,5exo)-5-(6, 7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;
(2endo3exo,5exo)-5-(6, 7-Dimethoxyquinoxalin-2-ylamino)-bicycio[2.2.1]heptane-2, 3-diol;
cis-2-(6-Methoxyquinoxalin-2-ylamino)-cyclopentanol;
trans-2-(6-Methoxyquinoxalin-2-ylamino)-cyclopentanol;
trans-4-(6-Methoxyquinoxalin-2-ylamino)-cyclohexanol;
[3aR,4S,6R,6aS]-6-(6,7-Dimethoxyquinoxalin-2-ylamino)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxole-4-carboxylic ethylamide;
2-(1,4-Dioxa-spiro[4,5]dec-8-yloxy)-6,7-dimethoxyquinoxaline;
4-(6,7-Dimethoxyquinoxalin-2-yloxymethyl)-cyclohexanol; 11
3-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol;
4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol:
5-(6,7-Dimethoxyquinoxalin-2-yloxy)-bicyclo[2.2.1]heptane-2,3-diol;
(2exo,3exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptane-2,3-diol;
Acetic acid cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester;
cis-4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol:
Dimethyl-carbamic acid 4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester;
trans-4-(6,7-Dimethoxy-4-oxyquinoxalin-2-ylamino)-cyclohexanol;
Acetic acid trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexyl ester;
(2exo,5exo)-5-(6,7)-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]-heptan-2-ol;
(2endo,5exo)-5-(6,7-Dimethoxyquinoline-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;
(2exo,6exo)-6-(6,7-Dimethoxyquinolin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;
4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(+)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(xe2x88x92)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(2cis, 4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(2cis,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
4-(6,7-Dimethylquinoxalin-2-ylamino)cyclohexanol; and
(1S,2R,4S,5R)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-Bicyclo[2.2.1]-heptan-2-ol.
More preferred compounds are the following:
trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;
cis-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;
4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(xe2x88x92)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;
(2exo, 5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;
trans-4-(7-Chloro-6-methoxyquinoxalin-2-ylamino)-cyclohexanol; and
4-(6,7-Dimethoxyquinolin-3-ylamino)-cyclohexanol; and
(1S,2R,4S,5R)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-Bicyclo[2.2.1]-heptan-2-ol.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
The compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates. Exemplary general procedures follow.
In addition, compounds of formula I are prepared according to the following Schemes I-X herein the variables are as described above, excepting those variables which one skilled in the art would appreciate would be incongruent with the method described. 
I. General Procedures:
1. Coupling of 2-chloro substituted quinoxaline and amines or anilines
A mixture of 2-chloro-6,7-dimethoxyquinoxaline (1 eq.) and an amine (about 1 to about 5 eq.) is heated at about 160 to about 180xc2x0 C. from about three hours to overnight. The dark-brown residue is dissolved in methanol/ methylene chloride (0%-10%) and chromatographed on silica gel eluted with hexane/ethyl acetate or methanol/methylene chloride (0%-100%) to yield the desired product. The desired product may be purified further through recrystallization in methanol, methylene chloride or methanol/water.
2. Coupling of 2-chloro substituted quinoxaline and alcohols or phenols
A suspension of an alcohol or mercaptan (1 eq.) and sodium hydride (about 1 to about 3 eq.) in anhydrous DMF/THF (0%-50%) is refluxed for 1 hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (1 eq.). The resulting mixture is refluxed for about one to about four hours. The suspension is neutralized to about pH 5-8 and partitioned between methylene chloride and brine. The residue after concentration of methylene chloride is chromatograplhed on silica gel eluted with hexane/ethyl acetate or methanol/methylene chloride (0%-100%) to give the desired product.
3. Reductive amination reaction with amino-quinolines and aldehydes or ketones.
An appropriately substituted 3-amino quinoline (1 eq.) is stirred with 1 eq. of the appropriate aldehyde or ketone in methanol (or another suitable solvent mixture) until TLC indicates imine formation is complete. Excess NaCNBH4 or NaBH4, or another suitable reducing agent is added and the mixture is stirred until TLC shows consumption of the intermediate imine. The mixture is concentrated and the residue is chromatographed on silica gel with hexane/ethyl acetate (0-100%) or chloroform/methanol (0-20%) to give the desired product.
4. coupling reaction of 3-amino substituted quinolines and bromophenyl compounds.
An appropriately substituted 3-amino quinoline (1 eq.) is stirred with xcx9c1.4 eq. of a strong base such as sodium t-butoxide, 1 eq. of the appropriate bromophenyl compound, and catalytic amounts of 2,2xe2x80x2-bis(diphenylphosphino)-1-1xe2x80x2-binaphthyl (S-BINAP) and bis(dibenzylideneacetone)-Palladium (Pd(dba)2) are mixed in an inert organic solvent such as toluene under an inert atmosphere such as argon and heated to about 80xc2x0 C. overnight. The mixture is cooled, diluted with a solvent such as ether, filtered, concentrated and chromatographed with 50% EtOAc/hexane to give the desired product.
5. Ether formation from 3-hydroxy substituted quinolines via Mitsunobu conditions.
A THF solution of an appropriately substituted hydroxyquinoxaline (at about 0 to about 25xc2x0 C.) is treated with 1 eq. each of the desired alcohol triphenylphosphine and finally diethylazodicarboxylate (DEAD) or a suitable equivalent. The reaction progress is monitored via TLC and upon completion of the reaction (about 1 to about 24 hours) the mixture is concentrated and the residue is chromatographed on silica gel to yield the desired product.
6. Dealkylation of a lower alkoxy substituted quinoline or quinoxalinie, and subsequent alkylation.
An appropriate lower alkoxy substituted quinoline or quinoxaline (1 eq.) in DMF is treated with excess sodium ethanthiolate (usually about 2 or more eq.) and the reaction mixture is stirred with heating from about 1 to about 24 hours. The mixture is partitioned between water and ethyl acetate. Extractive a workup followed by chromatography, if necessary, provides the corresponding desired hydroxy substituted quinoline or quinoxaline product.
The hydroxy substituted quinoline or quinoxaline product can be alkylated using the conditions for the Mitsunobu reaction as detailed above. Alternatively, simple alkylation using methods well-known in the art with a reactive alkyl- or benzyl-halide using NaH or another appropriate base in a suitable solvent provides the desired alkylated product.
7. Oxidation of a nitrogen in a quinoline or quinoxaline to the corresponding N-oxide.
An imine (xe2x95x90Nxe2x80x94) moiety in a quinoline or quinoxaline compound of formula (I), may be converted to the corresponding compound wherein the imine moiety is oxidized to an N-oxide, preferably by reacting with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fuinarate, maleate, methylene-bis-p-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The compounds of this invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived firom the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammiionia, triethylammonia, ethylenediamine, n-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylamnmonium hydroxide, and the like.
Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
The compounds of this invention can be regenerated from the base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g., hydrochloric acid.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
Compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration. It will also be apparent to those skilled in the art that certain compounds of formula I may exhibit geometrical isomerism. Geometrical isomers include the cis and trans forms of compounds of the invention, i.e., compounds having alkenyl moieties or substituents on the ring systems. In addition, bicyclo ring systems include endo and exo isomers. The present invention comprises the individual geometrical isomers, stereoisomers, enantiomers and mixtures thereof.
Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents, or by methods described according to the invention herein.
The present invention is further exemplified but not limited by the followina illustrative examples which describe the preparation of the compounds according to the invention.
Further, the following examples are representative of the processes used to synthesize the compounds of this invention.